An Extension to Study MA21573, Evaluating Tocilizumab in Patients With Active Rheumatoid Arthritis and an Inadequate Response to Current Non-Biological DMARDs and/or Anti-tumor Necrosis Factor (TNF) Therapy
- Registration Number
- NCT00883753
- Lead Sponsor
- Hoffmann-La Roche
- Brief Summary
This study was an extension to study MA21573 \[NCT00750880\], which was an open label single arm study to investigate the safety, tolerability and efficacy of tocilizumab monotherapy, or combination therapy with non-biological disease-modifying antirheumatic drugs (DMARDS), in patients with moderate to severe active rheumatoid arthritis. Patients who completed the 24 week core study, and had at least a moderate European League Against Rheumatism (EULAR) response, were eligible to enter this long-term extension study, and received tocilizumab 8 mg/kg intravenous (iv) every 4 weeks. The anticipated time on study treatment was 1-2 years, and the target sample size was \> 500 individuals.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 934
- patients who completed the 24-week MA21573 core study, had at least a moderate response based on EULAR definition criteria and no adverse events (AEs), serious adverse events (SAEs) or conditions that led to unacceptable risk of continued treatment.
-as for MA21573.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description tocilizumab tocilizumab [RoActemra/Actemra] Participants received tocilizumab 8 mg/kg intravenous (IV), maximum dose not exceeding 800 mg in a single infusion, every 4 weeks for up to 104 weeks or up to 4 weeks after tocilizumab became commercially available in the respective country whichever occurred first.
- Primary Outcome Measures
Name Time Method Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) 108 Weeks An AE was considered any unfavorable and unintended sign, symptom, or disease associated with the use of the study drug, whether or not considered related to the study drug. Preexisting conditions that worsened during the study and laboratory or clinical tests that resulted in a change in treatment or discontinuation from study drug were reported as adverse events. A SAE was any experience that: resulted in death, was life-threatening, required in-patient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect or was medically significant. The percentage of participants with AEs and SAEs that occurred in the Extension Study grouped according to the number of disease-modifying anti-rheumatic drugs (DMARD) a participant was taking at Core Baseline is presented.
- Secondary Outcome Measures
Name Time Method Percentage of Participants With Adverse Events Leading to Withdraw 108 Weeks An Adverse Event was considered any unfavorable and unintended sign, symptom, or disease associated with the use of the study drug, whether or not considered related to the study drug. Preexisting conditions that worsened during the study and laboratory or clinical tests that resulted in a change in treatment or discontinuation from study drug were reported as adverse events.
Time to Withdrawal Due to an Adverse Event (AE) 108 Weeks Time to withdrawal was defined as the number of days from Core Study Day 1 to the first date of onset of the AE leading to discontinuation of tocilizumab.
Percentage of Participants With Discontinuation of Treatment Due to Any Cause 108 Weeks Percentage of participants who discontinued treatment with tocilizumab for any reason.
Time to Discontinuation of Tocilizumab Treatment for Any Cause 108 Weeks Time in days from start of the Core Study Day 1 to discontinuation of tocilizumab for any reason.
Percentage of Participants With Marked Lipid Abnormalities 108 Weeks Fasting blood samples were collected for Lipids: Cholesterol, Triglyceride, High-density lipoprotein (HDL) Cholesterol, Low-density lipoprotein (LDL) Cholesterol every 12 weeks and at follow-up in the Extension study and were sent to a central laboratory for analysis. Lipid abnormalities were defined as a High Cholesterol, High Triglyceride, Low HDL Cholesterol and a High LDL Cholesterol that occurred at any time in the extension study.
Percentage of Participants With Adverse Events (AEs) of Special Interest 108 Weeks An Adverse Event was considered any unfavorable and unintended sign, symptom, or disease associated with the use of the study drug, whether or not considered related to the study drug. Preexisting conditions that worsened during the study and laboratory or clinical tests that resulted in a change in treatment or discontinuation from study drug were reported as adverse events. Adverse Events of special interest for this study were: Infections (preferred term in the infection adverse event group term), Serious Infections (an infection that qualified as Serious Adverse Event), Infusion Reactions (occurred during infusion or within 24 hours of infusion), Major Cardiac AE (Myocardial Infarction/ Acute Coronary Syndrome), Stroke or Death.
Percentage of Participants With ALT Elevations > 3*ULN 108 Weeks Blood samples were collected for the Liver Function Test: Alanine aminotransferase (ALT) every 12 weeks and at the follow-up visit in the Extension study and were sent to a central laboratory for analysis. Percentage of participants with any values greater than 3 times the Upper Limit of Normal (3\*ULN) is reported. ULN= 55 Units/Liter.
Percentage of Participants With AST Elevations > 3*ULN 108 Weeks Blood was collected for the Liver Function Test: Aspartate aminotransferase (AST) every 12 weeks and at the follow-up visit in the Extension study and were sent to a central laboratory for analysis. Percentage of participants with any values greater than 3 times the Upper Limit of Normal (3\*ULN) is reported. ULN= 40 Units/Liter.
Number of Participants Categorized by Highest Value for ALT (SGPT) During the Study 108 Weeks Blood samples were collected for liver function test: Alanine aminotransferase (serum glutamic-pyruvic transaminase) \[ALT(SGPT)\] every 12 weeks and at the follow-up visit in the Extension study and were sent to a central laboratory for analysis. The Upper Limit of Normal (ULN) for ALT=55 Units/Liter. The number of participants categorized by the highest value for ALT/GPT during the study is reported: Normal (ALT result within the central lab reference range), Greater than the ULN to 1.5 times the ULN (\>ULN to 1.5\*ULN), 1.5 times the ULN to 3 times the ULN (1.5\*ULN to 3\*ULN) and 3 times the ULN to 5 times the ULN (3\*ULN to 5\*ULN).
Number of Participants Categorized by Worst Value for AST (SGOT) During the Study 108 Weeks Blood samples were collected for liver function test: Aspartate aminotransferase (serum glutamic-oxaloacetic transaminase) \[AST (SGOT)\] every 12 weeks and at the follow-up visit in the Extension study and were sent to a central laboratory for analysis. The Upper Limit of Normal (ULN) for AST=40 Units/Liter. The number of participants categorized by worst value for AST(SGOT) during the study is reported: Normal (AST result is within the central lab reference range), Greater than the ULN to 1.5 times the ULN (\>ULN to 1.5\*ULN), 1.5 times the ULN to 3 times the ULN (1.5\*ULN to 3\*ULN) and 3 times the ULN to 5 times the ULN (3\*ULN to 5\*ULN).
Number of Participants Categorized by Worst Value for LDL Cholesterol During the Study 108 Weeks Blood samples were collected for LDL Cholesterol every 12 weeks and at the follow-up visit in the Extension study and were sent to a central laboratory for analysis. The number of participants categorized by the worst value for LDL Cholesterol during the study is reported: Low is below central lab reference range, Normal is within the central lab reference range and High is above central lab reference range.
Number of Participants Categorized by Worst Value for Total Cholesterol During the Study 108 Weeks Blood samples were collected for Total Cholesterol every 12 weeks and at the follow-up visit in the Extension study and were sent to a central laboratory for analysis. The number of participants categorized by worst value for Total Cholesterol during the study is reported: Low is below central lab reference range, Normal is within the central lab reference range and High is above central lab reference range.
Number of Participants Categorized by Worst Value for Neutrophil Count During the Study 108 Weeks Blood samples were collected for a Neutrophil Count every 12 weeks and at the follow-up visit in the Extension study and were sent to a central laboratory for analysis. The number of participants categorized by the worst value for Neutrophil Count during the study is reported: Low is below central lab reference range, Normal is within the central lab reference range and High is above central lab reference range.
Percentage of Participants With Clinically Meaningful Improvement in Disease Activity Score-28 (DAS28) Core Baseline, Extension Weeks 12, 24, 36, 48, 60, 72, 84, 96, 108 The DAS28 score is a measure of the patient's disease activity calculated using the tender joint count (TJC) \[28 joints\], swollen joint count (SJC) \[28 joints\], patient's global assessment of disease activity \[visual analog scale: 0=no disease activity to 100=maximum disease activity\] and the erythrocyte sedimentation rate (ESR) for a total possible score of 0 to approximately 10. Scores below 2.6 indicate best disease control and scores above 5.1 indicate worse disease control. Clinical meaningful improvement was defined as a ≥ 1.2 unit reduction in DAS28.
Percentage of Participants With DAS28 Low Disease Activity Extension Weeks 12, 24, 36, 48, 60, 72, 84, 96, 108 The DAS28 score is a measure of the patient's disease activity calculated using the tender joint count (TJC) \[28 joints\], swollen joint count (SJC) \[28 joints\], patient's global assessment of disease activity \[visual analog scale: 0=no disease activity to 100=maximum disease activity\] and the erythrocyte sedimentation rate (ESR) for a total possible score of 0 to approximately 10. Scores below 2.6 indicate best disease control and scores above 5.1 indicate worse disease control. Low Disease Activity was defined as a score of \< 3.2.
Percentage of Participants With DAS28 Remission Extension Weeks 12, 24, 36, 48, 60, 72, 84, 96, 108 The DAS28 score is a measure of the patient's disease activity calculated using the tender joint count (TJC) \[28 joints\], swollen joint count (SJC) \[28 joints\], patient's global assessment of disease activity \[visual analog scale: 0=no disease activity to 100=maximum disease activity\] and the erythrocyte sedimentation rate (ESR) for a total possible score of 0 to approximately 10. Scores below 2.6 indicate best disease control and scores above 5.1 indicate worse disease control. DAS28 Remission was defined as a DAS28 score \< 2.6.
Change From Baseline in DAS28 Core Baseline, Extension Weeks 12, 24, 36, 48, 60, 72, 84, 96, 108 The DAS28 score is a measure of the patient's disease activity calculated using the tender joint count (TJC) \[28 joints\], swollen joint count (SJC) \[28 joints\], patient's global assessment of disease activity \[visual analog scale: 0=no disease activity to 100=maximum disease activity\] and the erythrocyte sedimentation rate (ESR) for a total possible score of 0 to approximately 10. Scores below 2.6 indicate best disease control and scores above 5.1 indicate worse disease control. A negative change from Baseline indicated improvement.
Change From Baseline in Tender Joint Count Core Baseline, Extension Weeks 12, 24, 36, 48, 60, 72, 84, 96, 108 68 joints were assessed for tenderness and joints were classified as tender/not tender giving a total possible tender joint count score of 0 to 68. A negative change from Baseline indicated improvement.
Change From Baseline in Swollen Joint Count Core Baseline, Extension Weeks 12, 24, 36, 48, 60, 72, 84, 96, 108 66 joints were assessed for swelling and joints were classified as swollen/not swollen giving a total possible swollen joint count score of 0 to 66. A negative change from Baseline indicated improvement.
Change From Baseline in Patient Assessment of Pain Visual Analog Scale (VAS) Core Baseline, Extension Weeks 12, 24, 36, 48, 60, 72, 84, 96, 108 The patient assessed their pain using a 0 to 100 millimeter (mm) horizontal visual analogue scale (VAS). The left-hand extreme of the line equals 0 mm, and is described as "no pain" and the right-hand extreme equals 100 mm as "unbearable pain". A negative change from Baseline indicated improvement.
Change From Baseline in Patient Global Assessment of Disease Activity VAS Core Baseline, Extension Weeks 12, 24, 36, 48, 60, 72, 84, 96, 108 The patients global assessment of disease activity was assessed on a 0 to 100 millimeter (mm) horizontal visual analogue scale (VAS) by the patient. The left-hand extreme of the line equals 0 mm, and is described as "no disease activity" (symptom-free and no arthritis symptoms) and the right-hand extreme equals 100 mm, as "maximum disease activity" (maximum arthritis disease activity). A negative change from Baseline indicated improvement.
Change From Baseline in Physician Global Assessment of Disease Activity VAS Core Baseline, Extension Weeks 12, 24, 36, 48, 60, 72, 84, 96, 108 The physician global assessment of disease activity was assessed using a 0 to 100 mm horizontal visual analogue scale (VAS) by the physician. The left-hand extreme of the line equals 0 mm, and is described as "no disease activity" (symptom-free and no arthritis symptoms) and the right-hand extreme equals 100 mm, as "maximum disease activity" (maximum arthritis disease activity). A negative change from Baseline indicated improvement.
Change From Baseline in Erythrocyte Sedimentation Rate (ESR) Core Baseline, Extension Weeks 12, 24, 36, 48, 60, 72, 84, 96, 108 Blood was collected for Erythrocyte Sedimentation Rate (ESR) (a test that assesses tissue inflammation) and was analyzed at a local laboratory. ESR was measured in millimeters/hour (mm/hr). A reduction in the level is considered an improvement.
Change From Baseline in C-Reactive Protein (CRP) Core Baseline, Extension Weeks 12, 24, 36, 48, 60, 72, 84, 96, 108 Blood was collected for C-Reactive Protein (CRP) (a test for analysis of inflammatory and infectious disorders) and was analyzed at a central laboratory. The serum concentration of CRP was measured in milligrams/deciliter (mg/dL). A reduction in the level is considered an improvement.
Percentage of Participants With American College of Rheumatology 20 (ACR20) Response Core Baseline, Extension Weeks 12, 24, 36, 48, 60, 72, 84, 96, 108 ACR20 response was defined as a ≥ 20 % improvement (reduction) compared with baseline for both total joint count-68 joints (TJC68) and swollen joint count-66 joints (SJC66), as well as for three of the additional five ACR core set variables: Patient's Assessment of Pain over the previous 24 hours: using a Visual Analog Scale (VAS) left end of the line 0=no pain to right end of the line 100=unbearable pain; Patient's Global Assessment of Disease Activity and Physician's Global Assessment of Disease Activity over the previous 24 hours using a VAS where left end of the line 0=no disease activity to right end of the line 100=maximum disease activity; Health Assessment Questionnaire: 20 questions, 8 components: dressing/grooming, arising, eating, walking, hygiene, reach, grip and activities, 0=without difficulty to 3=unable to do; and acute-phase reactant \[either C-reactive protein or Erythrocyte Sedimentation Rate\].
Percentage of Participants With American College of Rheumatology 50 (ACR50) Response Core Baseline, Extension Weeks 12, 24, 36, 48, 60, 72, 84, 96, 108 ACR50 response is defined as a ≥ 50 % improvement (reduction) compared with baseline for both total joint count-68 joints (TJC68) and swollen joint count-66 joints (SJC66), as well as for three of the additional five ACR core set variables: Patient's Assessment of Pain over the previous 24 hours: using a Visual Analog Scale (VAS) left end of the line 0=no pain to right end of the line 100=unbearable pain; Patient's Global Assessment of Disease Activity and Physician's Global Assessment of Disease Activity over the previous 24 hours using a VAS where left end of the line 0=no disease activity to right end of the line 100=maximum disease activity; Health Assessment Questionnaire: 20 questions, 8 components: dressing/grooming, arising, eating, walking, hygiene, reach, grip and activities, 0=without difficulty to 3=unable to do; and acute-phase reactant \[either C-reactive protein or Erythrocyte Sedimentation Rate\].
Percentage of Participants With American College of Rheumatology 70 (ACR70) Response Core Baseline, Extension Weeks 12, 24, 36 ,48, 60, 72, 84, 96, 108 ACR70 response is defined as a ≥ 70 % improvement (reduction) compared with baseline for both total joint count-68 joints (TJC68) and swollen joint count-66 joints (SJC66), as well as for three of the additional five ACR core set variables: Patient's Assessment of Pain over the previous 24 hours: using a Visual Analog Scale (VAS) left end of the line 0=no pain to right end of the line 100=unbearable pain; Patient's Global Assessment of Disease Activity and Physician's Global Assessment of Disease Activity over the previous 24 hours using a VAS where left end of the line 0=no disease activity to right end of the line 100=maximum disease activity; Health Assessment Questionnaire: 20 questions, 8 components: dressing/grooming, arising, eating, walking, hygiene, reach, grip and activities, 0=without difficulty to 3=unable to do; and acute-phase reactant \[either C-reactive protein or Erythrocyte Sedimentation Rate\].
Percentage of Participants With American College of Rheumatology 90 (ACR90) Response Core Baseline, Extension Weeks 12, 24, 36 ,48, 60, 72, 84, 96, 108 ACR90 response is defined as a ≥ 90 % improvement (reduction) compared with baseline for both total joint count-68 joints (TJC68) and swollen joint count-66 joints (SJC66), as well as for three of the additional five ACR core set variables: Patient's Assessment of Pain over the previous 24 hours: using a Visual Analog Scale (VAS) left end of the line 0=no pain to right end of the line 100=unbearable pain; Patient's Global Assessment of Disease Activity and Physician's Global Assessment of Disease Activity over the previous 24 hours using a VAS where left end of the line 0=no disease activity to right end of the line 100=maximum disease activity; Health Assessment Questionnaire: 20 questions, 8 components: dressing/grooming, arising, eating, walking, hygiene, reach, grip and activities, 0=without difficulty to 3=unable to do; and acute-phase reactant \[either C-reactive protein or Erythrocyte Sedimentation Rate\].
Change From Baseline in Health Assessment Questionnaire Disability Index (HAQ-DI) Response Core Baseline, Extension Weeks 12, 24, 36 ,48, 60, 72, 84, 96, 108 The Stanford Health Assessment Questionnaire Disability Index (HAQ-DI) is a patient completed questionnaire specific for rheumatoid arthritis, consisting of 20 questions in 8 domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip and common daily activities. There are 4 possible responses for each question: 0=without any difficulty, 1=with some difficulty, 2=with much difficulty and 3=unable to do. The score for each of the domains is the highest (worst) score in each domain. A patient must have a domain score for at least 6 of 8 domains to calculate a valid HAQ-DI score which is the sum of domain scores, divided by the number of domains that have a score for a total possible score minimum/maximum 0 (best) to 3 (worst). A negative change from Baseline indicated improvement.
Percentage of Participants Achieving Clinical Meaningful Health Assessment Questionnaire Disability Index (HAQ-DI) Response Core Baseline, Extension Weeks 12, 24, 36 ,48, 60, 72, 84, 96, 108 The Stanford Health Assessment Questionnaire Disability Index (HAQ-DI) is a patient completed questionnaire specific for rheumatoid arthritis, consisting of 20 questions in 8 domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip and common daily activities. There are 4 possible responses for each question: 0=without any difficulty, 1=with some difficulty, 2=with much difficulty and 3=unable to do. The score for each of the domains is the highest (worst) score in each domain. A patient must have a domain score for at least 6 of 8 domains to calculate a valid HAQ-DI score which is the sum of domain scores, divided by the number of domains that have a score for a total possible score minimum/maximum 0 (best) to 3 (worst). Clinically meaningful improvement is defined as a reduction from Baseline in the HAQ-DI score ≥ 0.2.
Percentage of Participants Achieving Health Assessment Questionnaire Disability Index (HAQ-DI) Clinical Remission Extension Weeks 12, 24, 36 ,48, 60, 72, 84, 96, 108 The Stanford Health Assessment Questionnaire Disability Index (HAQ-DI) is a patient completed questionnaire specific for rheumatoid arthritis, consisting of 20 questions in 8 domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip and common daily activities. There are 4 possible responses for each question: 0=without any difficulty, 1=with some difficulty, 2=with much difficulty and 3=unable to do. The score for each of the domains is the highest (worst) score in each domain. A patient must have a domain score for at least 6 of 8 domains to calculate a valid HAQ-DI score which is the sum of domain scores, divided by the number of domains that have a score for a total possible score minimum/maximum 0 (best) to 3 (worst). Clinical Remission is defined as a HAQ-DI score \< 0.5.
Change From Baseline in Quality of Life Short Form (SF-36): Physical Component Score Core Baseline, Extension Weeks 12, 24, 36 ,48, 60, 72, 84, 96, 108 The SF-36 is a questionnaire used to assess physical functioning and is made up of eight domains: Physical Functioning, Role Physical, Bodily Pain, General Health, Vitality, Social Functioning, Role-Emotional and Mental Health. Transforming and standardizing these domains leads to the calculation of the Physical (PCS) and Mental (MCS) Component Summary measures. Scores ranging from 0 to 100, with 0=worst score (or quality of life) and 100=best score. A positive change from Baseline indicated improvement.
Change From Baseline in Quality of Life Short Form (SF-36):Mental Component Score Core Baseline, Extension Weeks 12, 24, 36 ,48, 60, 72, 84, 96, 108 The SF-36 is a questionnaire used to assess physical functioning and is made up of eight domains: Physical Functioning, Role Physical, Bodily Pain, General Health, Vitality, Social Functioning, Role-Emotional and Mental Health. Transforming and standardizing these domains leads to the calculation of the Physical (PCS) and Mental (MCS) Component Summary measures. Scores ranging from 0 to 100, with 0=worst score (or quality of life) and 100=best score. A positive change from Baseline indicated improvement.
Change From Baseline in FACIT-Fatigue Score Core Baseline, Extension Weeks 12, 24, 36 ,48, 60, 72, 84, 96, 108 FACIT-F is a 13-item questionnaire. Patients scored each item on a 5-point scale: 0 (Not at all) to 4 (Very much). The larger the patient's response to the questions (with the exception of 2 negatively stated), the greater the patient's fatigue. For all questions, except for the 2 negatively stated ones, the code was reversed and a new score was calculated as (4 minus the patient's response). The sum of all responses resulted in the FACIT-Fatigue score for a total possible score of 0 (worse score) to 52 (better score). A higher score reflects an improvement in the patient's health status. A positive change from Baseline indicated improvement.